Background and Aims: Hepatocyte apoptosis and fibrosis are both features of liver injury. However, the potential mechanistic link between these 2 processes remains obscure. Our aim was to ascertain if Fas-mediated hepatocyte apoptosis promotes liver fibrogenesis during extrahepatic cholestasis. Methods: Wild-type and Fas-deficient lymphoproliferation (Ipr) mice underwent bile duct ligation. Liver injury was assessed by quantitating hepatocyte apoptosis with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and determining serum ALT values. mRNA expression was quantitated using real-time polymerase chain reaction technology. Liver fibrosis was assessed by digital image analysis of Sirius red-stained sections. Results: In 3-day bile duct ligated (BDL) animals, TUNEL-positive hepatocytes and serum ALT values were reduced in Ipr versus wild-type animals. Likewise, hepatic mRNA transcripts for α-smooth muscle actin and platelet-derived growth factor receptor-β (initiation phase of stellate cell activation) and transforming growth factor β1 mRNA, collagen 1α, and tissue inhibitor of matrix metalloproteinases (perpetuation phase of stellate cell activation) were also reduced in 3-day BDL wild-type mice compared with Ipr mice. Finally, in 3-week BDL mice, immunoreactivity for α-smooth muscle actin and Sirius red staining for collagen were significantly less in Ipr compared with wild-type animals. Conclusion: Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. These observations suggest that inhibition of Fas-mediated apoptosis may be a therapeutic antifibrogenic strategy in cholestatic liver diseases.
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